Extended release, abuse deterrent pharmaceutical compositions

ABSTRACT

Pharmaceutical compositions comprising at least one active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof, at least one hydrophilic plastomer, at least one hydrophilic elastomer, and at least one deliquescent plasticizer, wherein the pharmaceutical compositions provide extended release of the API and have abuse deterrent properties. Methods for preparing the pharmaceutical compositions in which the components of the composition are humidified such that the deliquescent plasticizer deliquesces, thereby plasticizing the hydrophilic polymers.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.15/420,386, filed Jan. 31, 2017, which is a continuation of U.S.application Ser. No. 13/939,357, filed Jul. 11, 2013, now U.S. Pat. No.9,730,885, which claims priority to U.S. Provisional Application No.61/670,751, filed Jul. 12, 2012, and U.S. Provisional Application No.61/790,463, filed Mar. 15, 2013, the disclosure of each is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present disclosure generally relates to pharmaceutical compositionsthat provide extended release of active ingredients and have abusedeterrent properties.

BACKGROUND OF THE INVENTION

In 2008 it was reported that non-medical use of pain relievers among thepopulation aged 12 or older in the United States was second highest inprevalence among illicit drugs, after marijuana. Abuse of prescriptionpharmaceutical products follows the increasing availability of opioiddosage forms due to the more aggressive treatment of chronic pain in thepopulace. The increasing number of abusers, increasing availability, andthe destructive/addictive potential of opiates make prescriptionpharmaceutical abuse a matter of public health concern.

Several routes of administration are commonly attempted by abusers. Forexample, the pharmaceutical dosage form may be chewed, or it may becrushed or pulverized into a powder and administered intranasally (i.e.,snorted). Alternatively, the intact or tampered pharmaceutical dosageform may be dissolved in a suitable solvent and administeredparenterally (i.e., injected intravenously), or the intact or tampereddosage form may be smoked.

To deter misuse and/or abuse of pharmaceutical dosage forms withextended drug release, multiple strategies have been employed. First, achemical approach has been utilized to include an opioid antagonist inopioid pharmaceutical dosage forms. The opioid antagonist, which is notorally active, will substantially block the analgesic effects of theopioid when one attempts to abuse the tampered dosage form via snortingor injecting. Second, aversive agents and/or bitter agents have beenadded to pharmaceutical formulations to prevent abuse of the activepharmaceutical ingredient. This approach, however, could cause adverseeffects in the patient population due to the properties associated withthese agents. Third, a safer alternative is to incorporate excipientsthat provide a physical barrier in which abuse of the API is deterred.In one case, this is accomplished by incorporating the API into apolymeric matrix tablet containing high molecular weight gel formingpolymers such as polyethylene oxide. The polymeric matrix tablet hasincreased hardness and retains a plastic-like nature after curing at atemperature above the softening temperature of the polyethylene oxide.The resultant tablet dosage form is difficult to crush or chew and formsa viscous gel when the dosage form comes into contact with a suitablesolvent. However, because polyethylene oxide forms oxidative peroxideradicals when heated, APIs susceptible to oxidative degradation shouldbe incorporated into such dosage forms with care. Alternately, theconditions for curing the dosage form with an API sensitive to oxidationmust be tightly controlled, sometimes limiting the tamper resistantproperties thereof. Similarly, thermolabile APIs cannot be incorporatedinto these cured dosage forms.

To impart abuse deterrent properties to pharmaceutical dosage formscomprising polymers, the polymers generally need to be plasticized.Typically, polymers are plasticized by plasticizers using either of twocommonly used methods that thoroughly incorporate the plasticizers intothe polymers. The most common method is hot melt extrusion. In thisprocess, polymers and plasticizers are intimately mixed under heat andpressure and then extruded out of small orifices. Recent strides in thistechnique have resulted in acceptable material throughput for largescale manufacturing. A less common method for incorporating aplasticizer into a polymer involves dissolving the polymer and theplasticizer in a suitable co-solvent and then spray drying the mixture.This method has a very low material throughput and also has thesignificant technical issue of the plasticized polymers sticking to thespray drier. However, in both of these methods, the resultantplasticized polymer mass can be a sticky, non-flowable material thatposes additional processing problems in milling, blending, andcompressing with conventional manufacturing equipment.

Thus, there is a need for pharmaceutical dosage forms comprised ofpolymers that provide extended release of the API and are resistant toabuse and/or misuse. Additionally, there is a need for the easymanufacture of a plasticized polymer mass into a dosage form utilizingconventional processing equipment.

SUMMARY OF THE INVENTION

The present disclosure provides a tamper resistant, extended releasecomprising at least one active pharmaceutical ingredient (API) or apharmaceutically acceptable salt thereof, at least one hydrophilicplastomer, at least one hydrophilic elastomer, and at least onedeliquescent plasticizer. The pharmaceutical composition disclosedherein provides extended release of the API and has abuse deterrentproperties.

A further aspect of the present disclosure provides a process forpreparing a solid dosage form. The process comprises: (a) forming amixture comprising at least one hydrophilic plastomer, at least onehydrophilic elastomer, and at least one deliquescent plasticizer,wherein the mixture is a powder, a granulate, or a solid dosage unit;(b) humidifying the mixture of (a) to form a humidified powder, ahumidified granulate, or a humidified solid dosage unit; (c) optionallyforming the humidified powder or the humidified granulate into a treatedsolid dosage unit; (d) optionally coating the humidified solid dosageunit of (b) or the treated solid dosage unit of (c) to form a coatedsolid dosage unit; and (e) heating the humidified solid dosage unit of(b), the treated solid dosage unit of (c), or the coated solid dosageunit of (d) to form the solid dosage form.

Other aspects and iterations of the disclosure are described in moredetail below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows extended release of the API. Plotted is the mean percent invitro release of oxycodone HCl over a 12 hour period for prototype #1,prototype #2, a reference extended release (ER)/abuse deterrentformulation (ADF) oxycodone formulation, and a reference ER/non-ADFoxycodone formulation.

FIG. 2 illustrates abuse deterrent properties of the solid dosage form.Shown is the percent of particles retained on a 60 mesh screen (>250microns) after various grinding times for prototype #2, a referenceER/ADF oxycodone formulation, and a reference ER/non-ADF oxycodoneformulation.

FIG. 3 presents the force profile of the solid dosage form. Plotted isthe force (in Newtons) applied and the distance (in mm) compressed fortablets of three strengths of formulation prototype #3 and a referenceER/AFD oxycodone formulation. The breaking point refers to the point atwhich the force profile line deflects or plateaus.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides solid dosage pharmaceutical compositionsthat provide extended release of an active pharmaceutical ingredient andhave abuse deterrent properties. Also provided are methods for makingthe extended release, abuse deterrent pharmaceutical compositions. Thepharmaceutical compositions disclosed herein comprise at least onehydrophilic plastomer, optionally at least one hydrophilic elastomer,and at least one deliquescent plasticizer. Applicants of the presentinvention discovered that the hydrophilic polymers can be plasticizedwith deliquescent plasticizer by humidification of the compositioncomprising the polymers. Under a humid environment, the deliquescentplasticizer absorbs moisture from the atmosphere to become a liquid,thereby allowing the plasticizer to effectively plasticize thehydrophilic polymers. The humidified composition is then heated toremove excess moisture and to cure the hydrophilic polymers. Theresultant composition has sufficient hardness and resiliency such thatit resists being crushed or ground into fine particles.

(I) Pharmaceutical Composition

One aspect of the present disclosure provides extended release, abusedeterrent pharmaceutical compositions. Detailed below are the componentsof the composition, dosage forms of the composition, releasecharacteristics of the composition, and abuse deterrent properties ofthe composition.

(A) COMPONENTS OF THE COMPOSITION

The pharmaceutical composition disclosed herein comprises at least onehydrophilic plastomer, optionally at least one hydrophilic elastomer,and at least one deliquescent plasticizer. The combination ofhydrophilic plastomers and optional hydrophilic elastomer, when suitablyplasticized by the deliquescent plasticizer and heat-treated, creates afunctional abuse deterrent composition.

(i) Hydrophilic Plastomer

The pharmaceutical composition comprises at least one hydrophilicplastomer. The term “hydrophilic” refers to a substance with affinityfor water that readily absorbs and/or dissolves in water, and the term“plastomer” refers to a hard, rigid polymeric substance. Morespecifically, a hydrophilic plastomer refers to any polymeric substancethat imparts hardness to a solid dosage form matrix when plasticizedand/or cured.

The hydrophilic plastomer may be water soluble, water swellable,thermoplastic, or any combination thereof, and the hydrophilic plastomermay be natural, semi-synthetic, or synthetic. Non-limiting examples ofsuitable hydrophilic plastomers include cellulose ethers (such as, e.g.,hydroxypropyl cellulose (HPC), methyl cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC),carboxymethyl cellulose, and the like); polyalkylene oxides (such as,e.g., polyethylene oxide (PEO), polypropylene oxide, and copolymersthereof); polyalkylene glycols (such as, e.g., polyethylene glycol,polypropylene glycol, and copolymers thereof); polyolefinic alcohols(such as, e.g., polyvinyl alcohol); polyvinyl lactams (such as, e.g.,polyvinylpyrrolidone); polyvinyl alcohol/polyvinylpyrrolidonecopolymers; polycarboxylic acids; polysaccharides (such as, e.g.,celluloses, dextrans, gums derived from microbes or plants, starches,pectins, chitin, chitosan, and the like); polypeptides (such as, e.g.,gelatin, albumin, polylysine, soy protein, and so forth); andcombinations or copolymers of any of the foregoing. In exemplaryembodiments, the hydrophilic plastomer may be hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyethylene oxide, or combinationsthereof.

The hydrophilic plastomer may have a molecular weight ranging from about20,000 daltons (Da) to about 2,000,000 Da. In various embodiments, themolecular weight of the hydrophilic plastomer may range from about20,000 Da to about 100,000 Da, from about 100,000 Da to about 400,000Da, from about 400,000 Da to about 1,000,000 Da, or from about 1,000,000Da to about 2,000,000 Da. In one exemplary embodiment, the hydrophilicplastomer may have a molecular weight ranging from about 100,000 Da toabout 200,000 Da. In another exemplary embodiment, the hydrophilicplastomer may have a molecular weight ranging from about 800,000 Da toabout 900,000 Da.

The amount of hydrophilic plastomer present in the pharmaceuticalcomposition can and will vary depending upon the identity of thehydrophilic plastomer, as well as the identity and/or amount of theother components utilized in the pharmaceutical composition. In general,the amount of hydrophilic plastomer present in the pharmaceuticalcomposition may range from about 10% to about 90% by weight of thecomposition. In various embodiments, the amount of the hydrophilicplastomer present in the pharmaceutical composition may range from about10% to about 20%, from about 20% to about 30%, from about 30% to about40%, from about 40% to about 50%, or from about 50% to about 60%, fromabout 60% to about 70%, from about 70% to about 80%, or from about 80%to about 90% by weight of the pharmaceutical composition. In exemplaryembodiments, the amount of the hydrophilic plastomer present may rangefrom 30% to about 80% by weight of the pharmaceutical composition.

(ii) Hydrophilic Elastomer

The pharmaceutical composition disclosed herein may comprise at leastone hydrophilic elastomer. The term “elastomer” refers to a substancewith viscoelasticity, generally having a low Young's modulus (i.e., lowrigidity) and a high strain yield (i.e., high deformability). Theinclusion of a hydrophilic elastomer in the composition may counter thebrittleness of the hydrophilic plastomer(s).

The hydrophilic elastomer may be water soluble and/or water swellable;and the elastomer may be natural, semi-synthetic, or synthetic. As willbe appreciated by those skilled in the art, the molecular size of theelastomer can and will vary depending upon the identity of theelastomer. Suitable hydrophilic elastomers include, without limit,polyacrylates, polymethacrylates, combinations thereof, or copolymersthereof. Non-limiting examples of suitable polyacrylates includecarbomers, which are homopolymers of acrylic acid crosslinked with apolyalcohol allyl ether (e.g., allyl ether pentaerythritol, allyl etherof sucrose, allyl ether of propylene), and polycarbophil, which is ahomopolymer of acrylic acid crosslinked with divinyl glycol. Suitablehydrophilic methacrylate polymers include, but are not limited to,polyhydroxyethyl methacrylate, copolymers of methyl methacrylate andethyl acrylate, and the like. In one embodiment, the hydrophilicelastomer may be a carbomer.

The amount of hydrophilic elastomer present in the pharmaceuticalcomposition can and will vary depending upon the identity of thehydrophilic elastomer, as well as the identity and/or the amount of thehydrophilic plastomer(s) present in the pharmaceutical composition. Inembodiments in which the hydrophilic elastomer is present, the amount ofhydrophilic elastomer present in the pharmaceutical composition mayrange from about 0.5% to about 40% by weight of the composition. Invarious embodiments, the amount of hydrophilic elastomer present in thepharmaceutical composition may range from about 0.5% to about 2%, fromabout 2% to about 5%, from about 5% to about 10%, or from about 10% toabout 20%, or from about 20% to about 40% by weight of thepharmaceutical composition. In exemplary embodiments, the pharmaceuticalcomposition comprises the hydrophilic elastomer at an amount rangingfrom about 0.5% to about 10% by weight of the composition. In otherembodiments, the hydrophilic elastomer is not present.

(iii) Deliquescent Plasticizer

The pharmaceutical composition disclosed herein also comprises at leastone deliquescent plasticizer. In general, plasticizers increase theplasticity or fluidity of a material. A “deliquescent plasticizer”refers to a compound that is able to absorb moisture from the air suchthat it forms a saturated solution. Deliquescence occurs when thepartial vapor pressure of the deliquescent plasticizer is less than thepartial pressure of water vapor in the air. As a consequence, thedeliquescent plasticizer liquefies and its mobility increases. Thus, inthe pharmaceutical composition disclosed herein, humidification of amixture comprising the hydrophilic plastomer, the hydrophilic elastomer,and the deliquescent plasticizer allows the deliquescent plasticizer tobecome liquid such that it can incorporate into the hydrophilicplastomer and the hydrophilic elastomer, thereby plasticizing thehydrophilic plastomer and the hydrophilic elastomer.

The deliquescent plasticizer may be an organic acid, a sugar alcohol, aco-processed mixture of an organic acid and/or a sugar alcohol and aliquid plasticizer, or combinations thereof. Non-limiting examples ofsuitable organic acids include citric acid, glutaric acid, malic acid,tartaric acid, and the like. In one embodiment, the organic acid may becitric acid. Suitable sugar alcohols include, without limit, sorbitol,xylitol, maltitol, and the like. In another embodiment, the sugaralcohol may be sorbitol. In general, the organic acid and the sugaralcohol are in solid forms. Non-limiting examples of suitable liquidplasticizers include glycerol (glycerin), polyethylene glycols (e.g.,PEG 300, PEG 400, PEG 600, PEG 1000, etc.), triethyl citrate, tributylcitrate, acetyl triethyl citrate, triacetin (i.e., glycerol triacetal),dibutyl sebacate, diethyl phthalate, dibutyl phthalate, and combinationsthereof. In one embodiment, the co-processed mixture may comprisesorbitol and PEG. In another embodiment, the co-processed mixture maycomprise sorbitol and glycerol.

A co-processed mixture of an organic acid and/or a sugar alcohol and aliquid plasticizer may be prepared by contacting a solid form of theorganic acid and/or the sugar alcohol with the liquid plasticizer. Ingeneral, the liquid plasticizer contacts the surface of the solid formof the organic acid and/or the sugar alcohol. The ratio of the liquidplasticizer to the organic acid and/or the sugar alcohol can and willvary. For example, the ratio of the liquid plasticizer to the organicacid and/or the sugar alcohol may be about 1:99, about 5:95, about10:90, about 15:85, about 20:80, about 25:75, about 30:70, about 40:60,or any ratio there between. In some embodiments, the liquid plasticizermay be mixed with a suitable solvent. A suitable solvent is a solvent inwhich the liquid plasticizer dissolves, but the solid organic acidand/or sugar alcohol does not dissolve. Non-limiting examples ofsuitable solvents include alcohols, such as methanol, ethanol,isopropanol, propanol, and the like. In an embodiment in which theliquid plasticizer is glycerol, the solvent may be isopropanol. Contactbetween the liquid plasticizer and the solid form of the organic acidand/or the sugar alcohol may be performed in a fluid bed coater, a lowshear planetary mixer, or any other suitable device known in the art.

In exemplary embodiments, the deliquescent plasticizer may be citricacid, a combination of citric acid and sorbitol, or a combination ofcitric acid and a co-processed mixture of sorbitol and glycerol.

In embodiments in which the deliquescent plasticizer comprises anorganic acid, the amount of organic acid present in the pharmaceuticalcomposition may range from about 1% to about 20% by weight of thepharmaceutical composition. In various iterations, the amount of organicacid present in the pharmaceutical composition may range from about 1%to about 5%, from about 5% to about 10%, from about 10% to about 15%, orfrom about 15% to about 20% by weight of the pharmaceutical composition.

In embodiments in which the deliquescent plasticizer comprises a sugaralcohol, the amount of sugar alcohol present in the pharmaceuticalcomposition may range from about 1% to about 15% by weight of thepharmaceutical composition. In certain iterations, the amount of sugaralcohol present in the pharmaceutical composition may range from about1% to about 5%, from about 5% to about 10%, or from about 10% to about15% by weight of the pharmaceutical composition.

In embodiments in which the deliquescent plasticizer comprises aco-processed blend of a sugar alcohol and a liquid plasticizer, theamount of the co-processed blend present in the pharmaceuticalcomposition may range from about 5% to about 25% by weight of thepharmaceutical composition. In some iterations, the amount of theco-processed blend present in the pharmaceutical composition may rangefrom about 5% to about 10%, from about 10% to about 15%, from about 15%to about 20%, or from about 20% to about 25% by weight of thepharmaceutical composition.

The total amount of deliquescent plasticizer present in thepharmaceutical composition can and will vary depending upon theidentities and/or amounts of the hydrophilic plastomers and elastomerspresent in the pharmaceutical composition. In general, the total amountof the deliquescent plasticizer present in the composition may rangefrom about 2% to about 50% by weight of the pharmaceutical composition.In some embodiments, the total amount of the deliquescent plasticizerpresent may range from about 5% to about 40% by weight of thepharmaceutical composition. In other embodiments, the total amount ofthe deliquescent plasticizer present may range from about 10% to about30% by weight of the pharmaceutical composition. In various embodiments,the total amount of the deliquescent plasticizer present in thepharmaceutical composition may range from about 5% to about 10%, fromabout 10% to about 15%, from about 15% to about 20%, from about 20% toabout 25%, from about 25% to about 30%, from about 30% to about 40%, orfrom about 40% to about 50% by weight of the pharmaceutical composition.In exemplary embodiments, the total amount of the deliquescentplasticizer present may range from about 10% to about 30% by weight ofthe pharmaceutical composition.

(iv) Optional Modifying Agents

The pharmaceutical composition disclosed herein may optionally includeone or more modifying agents that improve the abuse deterrentproperties, add additional abuse deterrent features, and/or facilitatepreparation (e.g., manufacturability) of the pharmaceutical composition.The modifying agent may be a hydrophilic gelling polymer, a claymineral, a super-disintegrant, an alkalizing agent, a lubricant, orcombinations thereof.

Hydrophilic Gelling Polymer.

The optional modifying agent may be a hydrophilic gelling polymer.Hydrophilic gelling polymers, which are well known in the art, formviscous mixtures or gels when in contact with a suitable solvent.Inclusion of a gelling polymer may increase the gelling rate kineticsand/or overall gel viscosity when the pharmaceutical compositiondisclosed herein is in contact with a small volume of a suitablesolvent. As a consequence, the resultant viscous mixture is difficult todraw into a syringe, thereby making it difficult or impossible toinject. Thus, the presence of the hydrophilic gelling polymer mayprovide another tampering deterrent feature to the pharmaceuticalcomposition. Non-limiting examples of hydrophilic polymers are presentedabove in sections (I)(a)(i)-(ii). In one embodiment, the hydrophilicgelling polymer may be a cellulose ether. For example, the hydrophilicgelling polymer may be hydroxypropylmethyl cellulose (HPMC). Inexemplary embodiments, the hydrophilic gelling polymer may behydroxypropylmethyl cellulose having a molecular weight of about 150,000Da.

In embodiments in which the hydrophilic gelling polymer is included inthe pharmaceutical composition, the amount the hydrophilic gellingpolymer may range from about 0.1% to about 40% by weight of thepharmaceutical composition. In certain embodiments, the amount thehydrophilic gelling polymer may range from about 0.1% to about 5%, fromabout 5% to about 10%, from about 10% to about 20%, or from about 20% toabout 40% by weight of the pharmaceutical composition. In exemplaryembodiments in which the hydrophilic gelling polymer is included, theamount of the hydrophilic gelling polymer included in the pharmaceuticalcomposition may range from about 5% to about 20% by weight of thepharmaceutical composition.

Clay Mineral.

The optional modifying agent may be a clay mineral. As used herein, a“clay mineral” refers to a hydrated aluminum phyllosilicate or ahydrated magnesium silicate. In general, clay minerals comprise smallinsoluble particles. The clay mineral may be absorbent and/or adsorbent.Inclusion of a clay mineral may not only increase the tensile strengthof the pharmaceutical composition, but the clay mineral also may adsorbthe API when the pharmaceutical composition is in contact with a smallvolume of a suitable solvent. Additionally, the clay mineral may providea visual deterrent to tampering with the pharmaceutical compositionbecause the small clay particles form a cloudy suspension when incontact with a small volume of a suitable solvent.

Non-limiting examples of suitable clay minerals include talc, bentonites(such as sodium bentonite or calcium bentonite), kaolinites,nontronites, montmorillonites, pyrophyllites, saponites, sauconites,vermiculites, and combinations thereof. In a preferred embodiment, theclay mineral may be sodium bentonite. In embodiments in which the claymineral is present in the pharmaceutical composition, the amount of theclay mineral may range from about 0.1% to about 5% by weight of thepharmaceutical composition. In various embodiments, the amount of theclay mineral may range from about 0.1% to about 0.3%, from about 0.3% toabout 1%, or from about 1% to about 5% by weight of the pharmaceuticalcomposition.

Super-Disintegrant.

The optional modifying agent may be a super-disintegrant. Asuper-disintegrant may facilitate the gelling kinetics of thepharmaceutical composition when it is in contact with a small volume ofa suitable solvent, without affecting the extended release properties ofthe pharmaceutical composition. Non-limiting examples of suitablesuper-disintegrants include crospovidone, croscarmellose sodium,colloidal silicon dioxide, sodium starch glycolate, and low substitutedhydroxypropyl cellulose. In one embodiment, the super-disintegrant maybe crospovidone.

In embodiments in which the pharmaceutical composition includes asuper-disintegrant, the amount of the super-disintegrant may range fromabout 0.1% to about 10% by weight of the pharmaceutical composition. Incertain embodiments, the amount of the super-disintegrant may range fromabout 0.1% to about 0.3%, from about 0.3% to about 1%, from about 1% toabout 3%, or from about 3% to about 10% by weight of the pharmaceuticalcomposition. In exemplary embodiments, the amount of super-disintegrantincluded in the pharmaceutical composition may range from about 0.25% toabout 3% by weight of the pharmaceutical composition.

Alkalizing Agent.

The optional modifying agent may be an alkalizing agent. Inclusion of analkalizing agent may facilitate the gelling kinetics of the hydrophilicelastomer when the pharmaceutical composition is in contact with a smallvolume of a suitable solvent. Thus, the presence of the alkalizing agentmay provide additional abuse deterrent features to the pharmaceuticalcomposition. Non-limiting examples of suitable alkalizing agents includedi- and tri-basic phosphate salts (e.g., sodium or potassium phosphatedibasic, or sodium or potassium phosphate tribasic), bicarbonate salts(e.g., sodium or potassium bicarbonate), carbonate salts (e.g., sodiumor potassium carbonate), and combinations thereof. In exemplaryembodiments, the alkalizing agent may be potassium phosphate dibasic.

In embodiments in which the alkalizing agent is included in thepharmaceutical compositions, the amount of the alkalizing agent mayrange from about 0.1% to about 3% by weight of the pharmaceuticalcomposition. In various embodiments, the amount of the alkalizing agentmay range from about 0.1% to about 0.3%, from about 0.3% to about 1%, orfrom about 1% to about 3% by weight of the pharmaceutical composition.

Lubricant.

The optional modifying agent may be a lubricant, which facilitatespreparation of solid dosage forms of the pharmaceutical composition.Non-limiting examples of suitable lubricants include magnesium stearate,calcium stearate, zinc stearate, colloidal silicon dioxide, hydrogenatedvegetable oils, sterotex, polyoxyethylene monostearate, polyethyleneglycol, sodium stearyl fumarate, sodium benzoate, sodium lauryl sulfate,magnesium lauryl sulfate, and light mineral oil. In exemplaryembodiments, the lubricant may be magnesium stearate or colloidalsilicon dioxide.

In embodiments in which the lubricant is included in the pharmaceuticalcomposition, the amount of the lubricant may range from about 0.1% toabout 3% by weight of the pharmaceutical composition. In variousembodiments, the amount of the lubricant may range from about 0.1% toabout 0.3%, from about 0.3% to about 1%, or from about 1% to about 3% byweight of the pharmaceutical composition. In exemplary embodiments, theamount of the lubricant may be about 1% by weight of the pharmaceuticalcomposition.

(v) API

The pharmaceutical composition disclosed also comprises at least one APIor salt thereof. Suitable APIs include, without limit, opioid analgesicagents (e.g., adulmine, alfentanil, allocryptopine, allylprodine,alphaprodine, anileridine, aporphine, benzylmorphine, berberine,bicuculine, bicucine, bezitramide, buprenorphine, bulbocaprine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, myrophine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine,propoxyphene, sufentanil, tapentadol, tilidine, and tramadol);non-opioid analgesic agents (e.g., acetylsalicylic acid, acetaminophen,paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisol, naproxen,ketorolac, dichlophenac, tolmetin, sulindac, phenacetin, piroxicam, andmefamanic acid); anti-inflammatory agents (e.g., glucocorticoids such asalclometasone, fluocinonide, methylprednisolone, triamcinolone anddexamethasone; non-steroidal anti-inflammatory agents such as celecoxib,deracoxib, ketoprofen, lumiracoxib, meloxicam, parecoxib, rofecoxib, andvaldecoxib); antitussive agents (e.g., dextromethorphan, codeine,hydrocodone, caramiphen, carbetapentane, and dextromethorphan);antipyretic agents (e.g., acetylsalicylic acid and acetaminophen);antibiotic agents (e.g., aminoglycosides such as, amikacin, gentamicin,kanamycin, neomycin, netilmicin, streptomycin, and tobramycin;carbecephem such as loracarbef; carbapenems such as certapenem,imipenem, and meropenem; cephalosporins such as cefadroxil cefazolin,cephalexin, cefaclor, cefamandole, cephalexin, cefoxitin, cefprozil,cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone;macrolides such as azithromycin, clarithromycin, dirithromycin,erythromycin, and troleandomycin; monobactam; penicillins such asamoxicillin, ampicillin, carbenicillin, cloxacillin, dicloxacillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, andticarcillin; polypeptides such as bacitracin, colistin, and polymyxin B;quinolones such as ciprofloxacin, enoxacin, gatifloxacin, levofloxacin,lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and trovafloxacin;sulfonamides such as mafenide, sulfacetamide, sulfamethizole,sulfasalazine, sulfisoxazole, and trimethoprim-sulfamethoxazole;tetracyclines such as demeclocycline, doxycycline, minocycline, andoxytetracycline); antimicrobial agents (e.g., ketoconazole, amoxicillin,cephalexin, miconazole, econazole, acyclovir, and nelfinavir); antiviralagents (e.g., acyclovir, gangciclovir, oseltamivir, and relenza);steroids (e.g., estradiol, testosterone, cortisol, aldosterone,prednisone, and cortisone); amphetamine stimulant agents (e.g.,amphetamine and amphetamine-like drugs); non-amphetamine stimulantagents (e.g., methylphenidate, nicotine, and caffeine); laxative agents(e.g., bisacodyl, casanthranol, senna, and castor oil); anti-nauseaagents (e.g., dolasetron, granisetron, ondansetron, tropisetron,meclizine, and cyclizine); anorexic agents (e.g., fenfluramine,dexfenfluramine, mazindol, phentermine, and aminorex); antihistaminicagents (e.g., phencarol, cetirizine, cinnarizine, ethamidindole,azatadine, brompheniramine, hydroxyzine, and chlorpheniramine);antiasthmatic agents (e.g., zileuton, montelukast, omalizumab,fluticasone, and zafirlukast); antidiuretic agents (e.g., desmopressin,vasopressin, and lypressin); antimigraine agents (e.g., naratriptan,frovatriptan, eletriptan, dihydroergotamine, zolmitriptan, almotriptan,and sumatriptan); antispasmodic agents (e.g., dicyclomine, hyoscyamine,and peppermint oil); antidiabetic agents (e.g., methformin, acarbose,miglitol, pioglitazone, rosiglitazone, nateglinide, repaglinide,mitiglinide, saxagliptin, sitagliptine, vildagliptin, acetohexamide,chlorpropamide, gliclazide, glimepiride, glipizide, glyburide,tolazamide, and tolbutamide); respiratory agents (e.g., albuterol,ephedrine, metaproterenol, and terbutaline); sympathomimetic agents(e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, epinephrine,norepinephrine, dopamine, and ephedrine); H2 blocking agents (e.g.,cimetidine, famotidine, nizatidine, and ranitidine); antihyperlipidemicagents (e.g., clofibrate, cholestyramine, colestipol, fluvastatin,atorvastatin, genfibrozil, lovastatin, niacin, pravastatin, fenofibrate,colesevelam, and simvastatin); antihypercholesterol agents (e.g.,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,cholestyramine, colestipol, colesevelam, nicotinic acid, gemfibrozil,and ezetimibe); cardiotonic agents (e.g., digitalis, ubidecarenone, anddopamine); vasodilating agents (e.g., nitroglycerin, captopril,dihydralazine, diltiazem, and isosorbide dinitrate); vasoconstrictingagents (e.g., dihydroergotoxine and dihydroergotamine); anticoagulants(e.g., warfarin, heparin, and Factor Xa inhibitors); sedative agents(e.g., amobarbital, pentobarbital, secobarbital, clomethiazole,diphenhydramine hydrochloride, and alprazolam); hypnotic agents (e.g.,zaleplon, zolpidem, eszopiclone, zopiclone, chloral hydrate, andclomethiazole); anticonvulsant agents (e.g., lamitrogene,oxycarbamezine, phenytoin, mephenytoin, ethosuximide, methsuccimide,carbamazepine, valproic acid, gabapentin, topiramate, felbamate, andphenobarbital); muscle relaxing agents (e.g., baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, dantrolene sodium, metaxalone,orphenadrine, pancuronium bromide, and tizanidine); antipsychotic agents(e.g., phenothiazine, chlorpromazine, fluphenazine, perphenazine,prochlorperazine, thioridazine, trifluoperazine, haloperidol,droperidol, pimozide, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, melperone, and paliperidone); antianxiolitic agents (e.g.,lorazepam, alprazolam, clonazepam, diazepam, buspirone, meprobamate, andflunitrazepam); antihyperactive agents (e.g., methylphenidate,amphetamine, and dextroamphetamine); antihypertensive agents (e.g.,alpha-methyldopa, chlortalidone, reserpine, syrosingopine, rescinnamine,prazosin, phentolamine, felodipine, propanolol, pindolol, labetalol,clonidine, captopril, enalapril, and lisonopril); anti-neoplasia agents(e.g., taxol, actinomycin, bleomycin A2, mitomycin C, daunorubicin,doxorubicin, epirubicin, idarubicin, and mitoxantrone); soporific agents(e.g., zolpidem tartrate, eszopiclone, ramelteon, and zaleplon);tranquilizer agents (e.g., alprazolam, clonazepam, diazepam,flunitrazepam, lorazepam, triazolam, chlorpromazine, fluphenazine,haloperidol, loxapine succinate, perphenazine, prochlorperazine,thiothixene, and trifluoperazine); decongestant agents (e.g., ephedrine,phenylephrine, naphazoline, and tetrahydrozoline); beta blockers (e.g.,levobunolol, pindolol, timolol maleate, bisoprolol, carvedilol, andbutoxamine); alpha blockers (e.g., doxazosin, prazosin,phenoxybenzamine, phentolamine, tamsulosin, alfuzosin, and terazosin);non-steroidal hormones (e.g., corticotropin, vasopressin, oxytocin,insulin, oxendolone, thyroid hormone, and adrenal hormone); erectiledisfunction improvement agents; herbal agents (e.g., glycyrrhiza, aloe,garlic, nigella sativa, rauwolfia, St John's wort, and valerian);enzymes (e.g., lipase, protease, amylase, lactase, lysozyme, andurokinase); humoral agents (e.g., prostaglandins, natural and synthetic,for example, PGE1, PGE2alpha, PGF2alpha, and the PGE1 analogmisoprostol); psychic energizers (e.g., 3-(2-aminopropy)indole and3-(2-aminobutyl)indole); nutritional agents; essential fatty acids;non-essential fatty acids; vitamins; minerals; and combinations thereof.

Any of the above-mentioned APIs may be incorporated in thepharmaceutical composition described herein in any suitable form, suchas, for example, as a pharmaceutically acceptable salt, uncharged orcharged molecule, molecular complex, solvate or hydrate, prodrug, and,if relevant, isomer, enantiomer, racemic mixture, and/or mixturesthereof. Furthermore, the API may be in any of its crystalline,semi-crystalline, amorphous, or polymorphous forms.

In one embodiment, the API present in the pharmaceutical composition mayhave a potential for abuse. For example, the API may be an opioidanalgesic agent, a stimulant agent, a sedative agent, a hypnotic agent,an antianxiolitic agent, or a muscle relaxing agent.

In another embodiment, the API present in the pharmaceutical compositionmay be a combination of an opioid analgesic and a non-opioid analgesic.Suitable opioid and non-opioid analgesics are listed above.

In exemplary embodiments, the API in the pharmaceutical composition maybe an opioid analgesic. Exemplary opioid analgesics include oxycodone,oxymorphone, hydrocodone, hydromorphone, codeine, and morphine. In anexemplary embodiment, the API may be oxycodone hydrochloride. In anotherexemplary embodiment, the API may be oxymorphone hydrochloride.

The amount of API in the pharmaceutical composition can and will varydepending upon the active agent. In embodiments in which the API is anopioid analgesic, the amount of opioid in the pharmaceutical compositionmay range from about 2 mg to about 160 mg. In various embodiments, theamount of opioid in the pharmaceutical composition may range from about2 mg to about 10 mg, from about 10 mg to about 40 mg, from about 40 mgto about 80 mg, or from about 80 mg to about 160 mg. In certainembodiments, the amount of opioid in the pharmaceutical composition maybe about 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg,25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 60mg, 70 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg.

In embodiments in which the opioid is oxycodone hydrochloride, the totalamount of oxycodone hydrochloride present in the pharmaceuticalcomposition may range from about 2 mg to about 80 mg. In certainembodiments, the amount of oxycodone hydrochloride present in thepharmaceutical composition may range from about 2 mg to about 10 mg,from about 10 mg to about 30 mg, or from about 30 mg to about 80 mg. Inpreferred embodiments, the amount of oxycodone hydrochloride present inthe pharmaceutical composition may be about 5 mg, about 10 mg, about 15mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, or about 80 mg.

In embodiments in which the opioid is oxymorphone hydrochloride, thetotal amount of oxymorphone hydrochloride present in the pharmaceuticalcomposition may range from about 2 mg to about 80 mg. In certainembodiments, the amount of oxymorphone hydrochloride present in thepharmaceutical composition may range from about 2 mg to about 10 mg,from about 10 mg to about 30 mg, or from about 30 mg to about 80 mg. Inpreferred embodiments, the amount of oxymorphone hydrochloride presentin the pharmaceutical composition may be about 5 mg, about 10 mg, about20 mg, about 30 mg, or about 40 mg.

(vi) Optional Excipients

In various embodiments, the pharmaceutical composition disclosed hereinmay further comprise at least one additional pharmaceutically acceptableexcipient. Non-limiting examples of suitable excipients include binders,fillers, diluents, antioxidants, chelating agents, flavoring agents,coloring agents, taste masking agents, and combinations thereof.

In one embodiment, the excipient may be a binder. Suitable bindersinclude, but are not limited to, starches, pregelatinized starches,gelatin, polyvinylpyrrolidone, cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, ethyl cellulose, polyacrylamides,polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol,polyethylene glycol, polyols, saccharides, oligosaccharides,polypeptides, peptides, and combinations thereof.

In another embodiment, the excipient may be a filler. Suitable fillersinclude carbohydrates, inorganic compounds, and polyvinylpyrrolidone.For example, the filler may be calcium sulfate, calcium phosphate,calcium silicate, microcrystalline cellulose, starch, modified starches,lactose, sucrose, mannitol, sorbitol, or combinations thereof.

In another embodiment, the excipient may include a diluent. Non-limitingexamples of diluents suitable for use include pharmaceuticallyacceptable saccharides such as sucrose, dextrose, lactose,microcrystalline cellulose, fructose, xylitol, and sorbitol; polyhydricalcohols; starches; pre-manufactured direct compression diluents; andmixtures of any of the foregoing.

In yet another embodiment, the excipient may be an antioxidant. Suitableantioxidants include, without limit, ascorbyl palmitate, butylatedhydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole,butylated hydroxytoluene, sodium isoascorbate, dihydroguaretic acid,potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid,potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiarybutylphenol,alphatocopherol, and propylgallate.

In an alternate embodiment, the excipient may be a chelating agent.Non-limiting examples of suitable chelating agents includeethylenediamine tetracetic acid (EDTA) and its salts,N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid(NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,1,4,7,10-tetraazacyclodo-decane-N,N′,N″,N′″-tetraacetic acid,1,4,7,10-tetraaza-cyclododecane-N,N′,N″-triacetic acid,1,4,7-tris(carboxymethyl)-10-(2′-hydroxypropyl)-1,4,7,10-tetraazocyclodecane,1,4,7-triazacyclonane-N,N′,N″-triacetic acid,1,4,8,11-tetraazacyclotetra-decane-N,N′,N″,N′″-tetraacetic acid;diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,bis(aminoethanethiol)carboxylic acid, triethylenetetraamine-hexaaceticacid, and 1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid.

In a further embodiment, the excipient may be a flavoring agent.Flavoring agents may be chosen from synthetic flavor oils and flavoringaromatics and/or natural oils, extracts from plants, leaves, flowers,fruits, and combinations thereof.

In still another embodiment, the excipient may be a coloring agent.Suitable color additives include food, drug and cosmetic colors (FD&C),drug and cosmetic colors (D&C), or external drug and cosmetic colors(Ext. D&C).

In yet another embodiment, the excipient may be a taste-masking agent.Taste-masking materials include cellulose ethers; polyethylene glycols;polyvinyl alcohol; polyvinyl alcohol and polyethylene glycol copolymers;monoglycerides or triglycerides; acrylic polymers; mixtures of acrylicpolymers with cellulose ethers; cellulose acetate phthalate; andcombinations thereof.

The amount of excipient or excipients included in the pharmaceuticalcomposition can and will vary depending upon the identity and amounts ofthe components of the pharmaceutical composition as detailed above.

(vii) Optional Film Coating

In some embodiments, the pharmaceutical composition may further comprisean optional film coating. Typically, the film coating comprises at leastone water-soluble polymer, and the film coating does not affect theextended release or abuse deterrent properties of the pharmaceuticalcomposition. The film coating may provide moisture protection, enhancedappearance, increased mechanical integrity, improved swallowability,improved taste, and/or masking of odors.

Film coatings are well known in the art, e.g., some are commerciallyavailable, e.g., under the tradename OPADRY®. Typically, a film coatingcomprises at least one water-soluble polymer and at least oneplasticizer. Non-limiting examples of suitable polymers includehydroxypropylmethyl cellulose, hydroxypropyl cellulose,hydroxypropylethyl cellulose, ethyl cellulose, methyl cellulose,cellulose acetate phthalate, microcrystalline cellulose and carrageenan,acrylic polymers, polyvinyl alcohol, anionic and cationic polymers ofmethacrylic acid, copolymers of methacrylates, copolymers of acrylatesand methacrylates, copolymers of ethacrylate and methyl methacrylate,polyvinylacetate phthalate, and shellac. Examples of suitableplasticizers include, without limit, triethyl citrate (TEC),acetyltriethyl citrate (ATEC), acetyl tri-n-butyl citrate (ATBC),dibutyl sebacate, diethyl phthalate, and triacetin. The film coating mayoptionally comprise additional agents such as a coloring agent, afiller, a flavoring agent, a taste-masking agent, a surfactant, ananti-tacking agent, and/or an anti-foaming agent. Suitable examples ofthese agents are well known in the art and/or are detailed above.

(B) DOSAGE FORMS

The physical form of the pharmaceutical composition disclosed herein canand will vary. In general, the pharmaceutical composition is a soliddosage form. The solid dosage form may be one of various solid dosageunits. Non-limiting examples of suitable solid dosage units includetablets, compacts, pellets, caplets, pills, and capsules. Such dosageunits may be prepared using conventional methods known to those in thefield of pharmaceutical formulation and described in the pertinenttexts, e.g., in Gennaro, A. R., editor. “Remington: The Science &Practice of Pharmacy”, 21st ed., Williams & Williams, and in the“Physician's Desk Reference”, 2006, Thomson Healthcare. In general, thesolid dosage form is formulated for oral administration.

In exemplary embodiments, the solid dosage unit may be a tablet.Non-limiting types of tablets include coated tablets, uncoated tablets,compressed tablets, compacted tablets, molded tablets, layered tablets,bilayer tablets, extruded tablets, multiparticle tablets, monolithictablets, and matrix tablets. In exemplary embodiments, thepharmaceutical composition may be a solid dosage form comprising atablet.

In embodiments in which the solid dosage form is a tablet, the tabletgenerally has a friability of no greater than about 1.0%. In certainembodiments, the tablet may have a friability of less than about 1.0%,less than about 0.5%, less than about 0.3%, less than about 0.2%, lessthan about 0.1%, less than about 0.05%, or less than about 0.01%. Inexemplary embodiments, the tablet has a friability of zero.

(C) IN VITRO RELEASE PROPERTIES OF THE COMPOSITION

The solid dosage pharmaceutical composition disclosed herein isformulated such that the API in the composition is released over anextended period of time. For example, the total amount of API in thepharmaceutical composition may be released over a period of about 6hours, over a period of about 12 hours, over a period of about 18 hours,or over a period of about 24 hours. In exemplary embodiments, the totalamount of the API in the pharmaceutical composition may be releasedwithin about 8 hours to about 12 hours.

The in vitro dissolution of the API from the solid dosage pharmaceuticalcomposition disclosed herein may be measured using an approved USPprocedure. For example, dissolution may be measured using an USPapproved Type 2 paddle apparatus, at a paddle speed of 50 rpm or 100rpm, and a constant temperature of 37±0.5° C. The dissolution test maybe performed in the presence of 500 mL, 900 mL, or 1,000 mL of asuitable dissolution medium (e.g., having a pH from 1.0 to 6.8).Non-limiting examples of suitable dissolution media include water,phosphate buffer (pH 6.8), acetate buffer (pH 4.5), and 0.1N HCl.

In various embodiments, the in vitro release of the API from thepharmaceutical composition is such that no more than about 50%, 60%,70%, 80%, 90% or 95% of the API is released within about 6 hours. Inadditional embodiments, no more than about 80% of the API is releasedwithin about 6 hours. In still another embodiment, no more than about50%, 60%, 70%, 80%, 90% or 95% of the API is released within about 8hours.

(D) ABUSE DETERRENT PROPERTIES OF THE COMPOSITION

The solid dosage pharmaceutical compositions disclosed herein also haveabuse deterrent features. The combination of the plasticized hydrophilicplastomers and plasticized hydrophilic elastomers imparts sufficientmechanical integrity (i.e., strength, hardness, elasticity, etc.) to thecomposition such that it is resistant to crushing, grinding, cutting, orpulverizing to form a powder comprising small particles. Additionally,the composition comprises gelling polymers such that the compositionforms a viscous mixture or gel when in contact with a small volume of asuitable solvent.

The mechanical integrity of the solid dosage pharmaceutical compositionmay be assessed by measuring the particle size distribution aftercrushing, grinding, or pulverizing the composition in a suitableapparatus for a specified period of time. The composition may becrushed, ground, or pulverized in a pill crusher, a tablet grinder, aball mill, a co-mill, a high-shear mill, a coffee grinder, a blender, ahammer, or another apparatus to reduce particle size. In variousembodiments in which the composition is subjected to 12 minutes ofgrinding or milling to form particles, more than 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, or 95% of the particles may have an average diameterof at least about 250 microns. In further embodiments, in which thecomposition is subjected to 12 minutes of grinding or milling to formparticles, more than 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% ofthe particles may have an average diameter of at least about 500microns. Because the pharmaceutical composition disclosed herein isresistant to forming a fine powder, it deters abuse by inhalation.

Alternatively, the mechanical integrity of the pharmaceuticalcomposition may be accessed by measuring the breaking point or thebreaking strength of the solid dosage composition. The breaking strengthrefers to the amount of applied force needed to compromise the integrityof the solid dosage form. The breaking point may be determined from aforce profile of the composition. The force profile is a plot of forceversus compression distance in which changes in the thickness of thesolid dosage form are plotted as a function of increasing force appliedto the solid dosage form (Haslam et al., Int. J. Pharmaceut., 1998,173:233-242). The force profile may be generated using a TextureAnalyzer model TA.XT. Plus (Texture Technologies Corp.), an InstronUniversal Tester (Instron Engineering Corp.), or other suitableinstrument. Force is applied diametrically to the solid dosage form andthe compression distance is recorded. The breaking point exhibits itselfas the point in the force profile plot at which the ascending lineplateaus or descends in response to the application of increasing force(see FIG. 3). The breaking point may be expressed as force percompression distance.

Another method to determine the breaking point (or breaking strength)utilizes conventional hardness testers well known in the art.Appropriate models include, without limitation, Dr. Schleuniger® model8M (Pharmatron Inc.), Varian model VK200 (Varian Medical Systems Inc.),or Sotax HT1 (Sotax Corp.). In this analysis, when the integrity of thedosage form is compromised, the instrument will stop compressing andreport the force delivered to the dosage form at the breaking strength.In general, the pharmaceutical composition disclosed herein has abreaking strength of less than about 500 Newtons (N). In variousembodiments, the breaking strength of the pharmaceutical composition isless than about 400 N, less than about 350 N, less than about 300 N,less than about 250 N, or less than about 200 N. As additional force isapplied beyond the breaking point, the composition continues to flattenor deform, which is indicative of plastic deformation.

An additional abuse deterrent property is that the pharmaceuticalcomposition, whether whole, flattened, or broken into large particles,forms a viscous mixture or gel when in contact with a small volume of asuitable solvent. The volume of the suitable solvent may range fromabout 1 mL to about 10 mL. For example, the volume may be about 2 mL,about 3 mL, about 4 mL about 5 mL, about 6 mL, about 7 mL, about 8 mL,about 9 mL, or about 10 mL. Suitable solvents include water, alcoholssuch as ethanol, acids such as acetic acid, fruit juice, and mixtures ofany of the foregoing. The resultant gel has a high viscosity thatprevents separation of the active ingredient from the viscous gel,provides a visual deterrence to injection abuse, and inhibits the gelledmixture from being drawn through an injection syringe needle.Consequently, the pharmaceutical compositions disclosed herein providedeterrence to abuse by extraction of the API and consequent injection ofthe extracted mixture.

(E) EXEMPLARY EMBODIMENTS

In one exemplary embodiment, the hydrophilic plastomer compriseshydroxypropyl cellulose, hydroxypropylmethyl cellulose, and polyethyleneoxide, and is present in an amount ranging from about 50% to about 80%by weight of the composition; the optional hydrophilic elastomer ispresent and is a carbomer present in an amount ranging from about 0.5%to about 10% by weight of the composition; the deliquescent plasticizercomprises citric acid and sorbitol, and is present in an amount rangingfrom about 10% to about 30% by weight of the composition; the optionallubricant is magnesium stearate; the API is chosen from oxycodone,oxymorphone, hydrocodone, hydromorphone, codeine, and morphine; and thecomposition is a solid dosage form.

(II) Process for Preparing Solid Dosage Pharmaceutical Compositions

Another aspect of the disclosure encompasses a process for preparing asolid dosage form of the pharmaceutical composition disclosed herein.The process comprises: (a) forming a mixture comprising at least onehydrophilic plastomer, optionally at least one hydrophilic elastomer,and at least one deliquescent plasticizer, wherein the mixture is apowder, a granulate, or a solid dosage unit; (b) humidifying the mixtureof (a) to form a humidified powder, a humidified granulate, or ahumidified solid dosage unit; (c) optionally forming the humidifiedpowder or the humidified granulate into a treated solid dosage unit; (d)optionally coating the humidified solid dosage unit of (b) or thetreated solid dosage unit of (c) to form a coated solid dosage unit; and(e) heating the humidified solid dosage unit of (b), the treated soliddosage unit of (c), or the coated solid dosage unit of (d) to form thesolid dosage form.

(a) Forming the Mixture

The first step of the process comprises forming a mixture comprising atleast one hydrophilic plastomer, optionally at least one hydrophilicelastomer, and at least one deliquescent plasticizer, which are detailedabove in sections (I)(a)(i)-(iii), respectively. In some embodiments,the mixture may further comprise at least one API and/or at least onemodifying agent, as detailed above in sections (i)(a)(v) and (iv),respectively.

The mixture may be a powder, a granulate, or a solid dosage unit. Asmentioned above in section (I)(b), suitable solid dosage units includetablets, compacts, pellets, caplets, pills, and capsules. In someembodiments, the components of the mixture may be blended, mixed, rollercompacted, milled, and/or granulated, thereby forming a blend or agranulate. All these procedures are well known in the art. In otherembodiments, the blend or granulate may be formed into a solid dosageunit using techniques well known in the art.

(b) Humidifying the Mixture

The process further comprises humidifying the mixture of (a) to form ahumidified powder, a humidified granulate, or a humidified solid dosageunit. During this step of the process, the partial pressure of the watervapor in the atmosphere exceeds the partial water vapor pressure of thedeliquescent plasticizer such that the deliquescent plasticizer absorbsmoisture from the atmosphere and forms a saturated solution. As aconsequence, the mobility of the plasticizer increases such that it canincorporate into the hydrophilic plastomer and elastomer, therebyplasticizing the hydrophilic plastomer and elastomer. As detailed belowin Example 5, the humidification step increases the mechanical integrityof the solid dosage form, and consequently increases the abusedeterrence of the solid dosage form of the pharmaceutical composition.

The temperature and relative humidity at which the humidification stepoccurs can and will vary depending mainly upon the identity of thedeliquescent plasticizer. Each deliquescent plasticizer deliquesces at aparticular level or range of relative humidity. For example, citric aciddeliquesces at about 75% relative humidity at 25° C., and sorbitoldeliquesces from about 69% to about 91% relative humidity at 25° C.

In various embodiments, the humidification step may occur at a relativehumidity that ranges from about 40% to about 100% at 25° C. In someembodiments, the relative humidity may range from about 40% to about 50%at 25° C., from about 50% to about 60% at 25° C., from about 60% toabout 70% at 25° C., from about 70% to about 80% at 25° C., from about80% to about 90% at 25° C., or from about 90% to about 100% at 25° C. Inexemplary embodiments, the relative humidity during the humidificationstep may range from about 65% to about 85% at 25° C.

The temperature of the humidification step also may vary. In general,the humidification step may occur at a temperature ranging from about 5°C. to about 90° C. In certain embodiments, the temperature of thehumidification step may range from about 5° C. to about 15° C., fromabout 15° C. to about 30° C., from about 30° C. to about 60° C., or fromabout 60° C. to about 90° C. In exemplary embodiments, the temperatureof the humidification step may range from about 30° C. to about 50° C.

The duration of the humidification step can and will vary depending uponthe components of the pharmaceutical composition and the humidificationconditions. In general, the duration of the humidification step mayrange from several minutes to several hours. For example, the durationof the humidification step may range from about 10 minutes to about 1hour, from about 1 hour to about 2 hours, or from about 2 hours to about5 hours. In one exemplary embodiment, the duration of the humidificationstep may be about 2 hours.

The powder, granulate, or solid dosage form may be humidified in a pancoater unit, an oven, a humidifier, a humidification chamber, aV-blender, or other suitable apparatus known in the art.

The humidified solid dosage unit may be dried prior to the optionalcoating step (d). The temperature of the drying step may vary. Ingeneral, the drying step may occur at a temperature ranging from about5° C. to about 90° C. In certain embodiments, the temperature of theoptional drying step may range from about 5° C. to about 15° C., fromabout 15° C. to about 30° C., from about 30° C. to about 60° C., or fromabout 60° C. to about 90° C. In exemplary embodiments, the temperatureof the drying step may range from about 30° C. to about 50° C. Optionaluse of nitrogen or vacuum assisted drying techniques will lower thetemperature and time requirements needed to effect drying and is assumedto be included in the body of this work as obvious to someone versed inthe art.

The duration of the drying step can and will vary depending upon thecomponents of the pharmaceutical composition and the humidificationconditions. In general, the duration of the drying step may range fromseveral minutes to several hours. For example, the duration of thedrying step may range from about 10 minutes to about 1 hour, from about1 hour to about 2 hours, or from about 2 hours to about 5 hours. In oneexemplary embodiment, the duration of the humidification step may beabout 2 hours

(c) Optionally Forming a Solid Dosage Unit

In embodiments in which the mixture from step (a) comprises a powder ora granulate, the humidified powder or the humidified granulate formedduring step (b) may be optionally mixed with at least one API and/or atleast one modifying agent and formed into a treated solid dosage unitusing procedures well known in the art.

(d) Optionally Coating the Solid Dosage Unit

The process further comprises an optional step in which the humidifiedsolid dosage unit from step (b) or the treated solid dosage unit fromstep (c) is coated with a film coating to form a coated solid dosageform. Examples of suitable film coatings are detailed above in section(I)(a)(vii). The optional coating step prevents agglomeration orsticking among individual solid dosage forms and sticking between thesolid dosage forms and the equipment. The film coating may be spraycoated onto the solid dosage form. The spray coating system by be abottom spray coating system, a top spray coating system, a tangentialspray coating system, a pan coating system, or another suitable coatingsystem.

(e) Heating the Solid Dosage Unit

The final step of the process comprises heating the humidified soliddosage unit from step (b), the treated solid dosage unit from step (c),or the coated solid dosage unit from step (d) to form the solid dosageform. This heating step essentially cures the hydrophilic plastomer inthe solid dosage unit matrix that has a softening temperature below theselected temperature. The heating step may also remove excess moisturefrom the dosage unit retained from the humidification step. The soliddosage form prepared by the process disclosed herein has sufficientmechanical integrity such that it is resistant to crushing, cutting,milling, pulverizing, or other means of tampering.

In general, the heating step occurs at a temperature greater than about50° C. For example, the humidified or treated solid dosage units may beheated to a temperature greater than about 50° C., greater than about60° C., greater than about 70° C., greater than about 80° C., greaterthan about 90° C., or greater than about 100° C. In exemplaryembodiments, the temperature of the heating step may range from about60° C. to about 90° C.

The duration of the heating step can and will vary depending upon thecomponents of the pharmaceutical composition. The duration of theheating step may range from about 10 minutes to about 10 hours. Ingeneral, the higher the temperature, the shorter the duration of time.For example, the solid dosage unit may be heated to a temperature ofabout 80° C. for about 3 hours, or the solid dosage unit may be heatedto a temperature of about 90° C. for about 1 hour.

(f) Iterations of the Process

Persons skilled in the art will appreciate that different components ofthe pharmaceutical composition may be introduced at various pointsduring the process for preparing a solid dosage form of thepharmaceutical composition. Table A lists non-limiting examples ofvarious iterations of the process.

TABLE A Possible Iterations # Details of Process* 1 granulate a + b +c + d → add e → form tablet → humidify → (optional coat) → heat 2granulate a + b + c + d + e → form tablet → humidify → (optional coat) →heat 3 granulate a + b + c + d → humidify → add e → form tablet →(optional coat) → heat 4 granulate d + b + c → add e → form tablet →humidify → (optional coat) → heat 5 granulate d + b + c + e → formtablet → humidify → (optional coat) → heat 6 granulate d + b + c →humidify → add e → form tablet → (optional coat) → heat 7 granulate d +f + b + c → add e → form tablet → humidify → (optional coat) → heat 8granulate d + f + b + c + e → form tablet → humidify → (optional coat) →heat 9 granulate d + f + b + c → humidify → add e → form tablet →(optional coat) → heat 10 blend d + f + b + c + e → form tablet →humidify → (optional coat) → heat 11 blend d + f + b + c + e → humidify→ form tablet → (optional coat) → heat 12 blend d + f + b + c → humidify→ add e → form tablet → (optional coat) → heat 13 blend a + b + c + d +e → form tablet → humidify → (optional coat) → heat 14 blend a + b + c +d + e → humidify → form tablet → (optional coat) → heat 15 blend a + b +c + d → humidify → add e → form tablet → (optional coat) → heat *a =co-processed mixture of sorbitol and glycerol b = hydrophilic plastomerc = hydrophilic elastomer d = citric acid e = API f = sorbitol

Definitions

Compounds useful in the compositions and methods include those describedherein in any of their pharmaceutically acceptable forms, includingisomers such as diastereomers and enantiomers, salts, solvates, andpolymorphs, as well as racemic mixtures and pure isomers of thecompounds described herein, where applicable.

When introducing elements of the present invention or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

The term “about,” particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples represent techniquesdiscovered by the inventors to function well in the practice of theinvention. Those of skill in the art should, however, in light of thepresent disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention, therefore all matter set forth is to be interpreted asillustrative and not in a limiting sense.

Example 1: Preparation of Prototype #1

A first prototype of the disclosed extended release (ER), abusedeterrent formulation (ADF) was prepared in which the plasticizercomprised a combination of citric acid and a co-processed mixture ofsorbitol and glycerol. The co-processed plasticizer (90% sorbitol/10%glycerol) was prepared by spraying a solution of 30% glycerol/70%isopropyl alcohol onto sorbitol powder using a suitable fluid bedcoating unit or low shear planetary mixer. A mixture comprising highmolecular weight hydroxypropyl cellulose (25-35% w/w), carbomer (2-4%w/w), citric acid (1-10% w/w), co-processed sorbitol/glycerol (10-20%w/w) was roller compacted to an appropriate ribbon thickness. Theribbons were milled to an appropriate particle size, which were then dryblended with hydroxypropylmethyl cellulose (1-10% w/w), polyethyleneoxide (15-25% w/w), and oxycodone hydrochloride (40 mg). The blend waslubricated with Mg stearate (1% w/w), and the lubricated blend wascompacted into tablets using an automated press. The tablets werehumidified in a pan coater with clean steam for 2 hours at 45° C. andbetween 65% to 99% relative humidity, cured in the pan coater at 80° C.for 3 hours, and then coated with a non-functional appearance coating.

Example 2: Preparation of Prototype #2

A second prototype of the extended release, abuse deterrent formulationwas prepared in which the plasticizer comprised a combination of citricacid and sorbitol. A mixture comprising high molecular weighthydroxypropyl cellulose (25-35% w/w), carbomer (2-4% w/w), citric acid(5-15% w/w), sorbitol (1-10% w/w) was roller compacted to theappropriate ribbon thickness. The ribbons were milled to the appropriateparticle size, which were then dry blended with hydroxypropylmethylcellulose (1-10% w/w), polyethylene oxide (15-25% w/w), and oxycodonehydrochloride (40 mg). The blend was lubricated with Mg stearate (1%w/w), and the lubricated blend was compacted into tablets using anautomated press. The tablets were humidified in a pan coater with cleansteam for 2 hours at 45° C. and between 65% to 99% relative humidity,cured in the pan coater at 80° C. for 3 hours, and then coated with anon-functional appearance coating.

Example 3: In Vitro Release of Oxycodone from Prototypes #1 and #2

The in vitro dissolution of oxycodone from prototypes #1 and #2 wasmeasured in 900 mL phosphate buffer (pH 6.8) or 0.1N HCl using an USPtype 2 paddle apparatus with a paddle speed of 50 rpm and a constanttemperature of 37° C. In some instances, the tablets (n=3) were placedin sinkers to prevent flotation. Samples were removed at various timepoints from 0.5 to 12 hr and analyzed by HPLC for oxycodonehydrochloride. FIG. 1 presents the dissolution profiles of prototypes #1and #2, as well as those of a reference ER, ADF oxycodone (40 mg)formulation and a reference ER, non-ADF oxycodone (40 mg) formulation.The release of oxycodone from the prototypic preparations occurred overan extended period of time (see Table 1). For example, no more thanabout 80% of oxycodone was released within about 4 hours and no morethan about 90% of the oxycodone was released within about 6 hours.

TABLE 1 In Vitro Release of Oxycodone Reference ER, Reference ER,Prototype #1 Prototype #2 ADF non-ADF Time (hrs) (mean %) (mean %) (mean%) (mean %) 0.5 25.1 25.5 18.03 23.77 1 36.0 36.7 28.80 37.55 2 51.252.1 45.42 57.28 4 71.6 72.0 70.24 82.65 6 86.3 85.1 85.92 96.27 8 94.492.5 94.25 102.24 10 98.1 96.4 98.13 104.26 12 99.7 97.9 99.98 105.19

Example 4: Physical Properties of the Prototypic Formulations

The abuse deterrence properties of prototypes #1 and #2 were compared tothose of the reference ER, ADF oxycodone formulation and the referenceER, non-ADF oxycodone formulation. For this, each tablet was flattenedin a hardness tester, the flattened tablet was twisted to form a“butterfly,” and the butterflied tablet was then milled in an IKA 10Amill at 1 minute intervals for up to 15 minutes total. At relevant timepoints, the milled tablet was analyzed for particle size distributionusing a Sonic Sifter with a screen mesh size of 35 mesh (500 microns),60 mesh (250 microns), and 120 mesh (125 microns).

Table 2 presents the percent of particles retained on each screen orpassed through the 120 mesh screen for each sample after 12 minutes ofmilling. For both prototypes #1 and #2, more than 80% of the particleshad an average diameter of greater than 500 microns, whereas for both ofthe reference formulations less than 10% of the particles had an averagediameter of greater than 500 microns.

TABLE 2 Particle Size Distribution After 12 Minutes of Milling 35 Mesh60 Mesh <120 Mesh (>500 (>250 120 Mesh (<125 microns) microns) microns)(>125 microns) (% passed Sample (% retained) (% retained) (% retained)through) Prototype 89.05 96.02 96.02 0 #1 Prototype 84.58 94.03 97.01 0#2 Reference 6.8 41.5 89.0 14.4 ER, ADF Reference 1.2 3.5 17.4 82.6 ER,Non-ADF

FIG. 2 presents the percentage of particles retained on the 60 meshscreen as the milling time increased from 1 minute to 15 minutes forprototype #2 and the two reference formulations. Even after 15 minutesof milling, nearly 90% of the particles derived from prototype #2 had anaverage diameter of greater than 250 microns, whereas only about 30% ofthe particles derived from the reference ER, ADF had particle sizesgreater than 250 microns.

Example 5: Effect of Humidifying the Prototypic Formulations

The humidification step is a transformative event in the preparation ofthe formulations disclosed herein. In this step, the deliquescentplasticizers adsorb water to the point of forming a saturated solution(all or in part) and increase in mobility. This allows for sufficientplasticization of the target polymers while in the blend, granulate, ortablet state. To investigate the effect of humidification, the physicalproperties of prototypes #1 and #2 were examined after beingprepared: 1) with no humidification and curing steps; 2) with a curingstep but no humidification step; and 3) with both humidification andcuring steps. The physical properties of each tablet was measured byflattening the tablet in a hardness tester, measuring the thickness ofthe flattened tablet, butterflying the flattened tablet, and milling thebutterflied tablet as described above in Example 4.

As shown in Table 3, the hardness of the tablets increased from lessthan about 25 kp (250N) to greater than about 85 kp (850N) whenhumidification was incorporated into the manufacturing process.

TABLE 3 Effect of Humidification on the Tamper Resistant PropertiesPhysical evaluation (% retained) Hardness Tester 35 Mesh 60 Mesh 120Mesh Hardness Thickness (>500 (>250 (>125 Prototype (kp) (mm) microns)microns) microns) 1* 6.2 Broke into 5.21 16.67 44.27 2 pieces 1** 7.87.35 72.68 90.21 95.88 1*** 85.5 3.04 89.05 96.02 96.02 2* 12.5 Brokeinto 6.32 23.56 61.49 2 pieces 2** 23.8 5.91 88.72 95.38 95.90 2*** 85.53.46 84.58 94.03 97.01 *= “As-is” (No humidification, no curing) **=Cured only (No Humidification) ***= Humidified and cured

Example 6: Syringeability of the Prototypic Formulation

The combination of plasticized hydrophilic plastomers and elastomers inthe pharmaceutical composition disclosed herein provides abuse deterrentproperties. As demonstrated above in Examples 4 and 5, when properlyplasticized, the prototypic formulation has sufficient hardness andtensile strength such that it is resistant to crushing, grinding,cutting, or pulverizing to form a powder comprising small particles.Additionally, the formulation comprises gelling polymers such that itforms a viscous mixture or gel when in contact with a small volume of asuitable solvent.

To measure syringeability, ground tablets were hydrated in 5 mL of waterwhile stirring for 1 minute, 3 minutes, or 5 minutes. A 1 mL syringewith a 27 gauge needle connected to an appropriate instrument to measureforce (Texture Analyzer) was used to pull the sample up into the syringebarrel. The amount of solution aspirated into the needle was recordedand then analyzed via HPLC to determine the oxycodone HCl content. Theresults for the prototypic formulation, the reference ER, ADF oxycodoneformulation, and the reference ER, non-ADF oxycodone formulation areshown in Table 4. Very little oxycodone was detected in the mixturesderived from the prototype formulation.

TABLE 4 Syringeability Volume recovered Oxycodone HCl (mL) recovered(mg) Sample 1 min 3 min 5 min 1 min 3 min 5 min Prototype Formulation 10.66 0.46 0.13 0.17 0.05 Reference ER, ADF 1 0.65 0.4 1.74 1.58 0.72Reference ER, Non-ADF 0.05 0.1 0.02 2.53 1.38 1.2

Another method for testing the injectabilty of a pharmaceuticalcomposition is to determine the amount of freely soluble drug present insmall volumes regardless of polymer entrapment. In this test, wholetablets, or tablets cut into 16 pieces were hydrated with 2 mL, 5 mL or10 mL of water and the mixture was stirred for 5 min, 10 min, or 30 min.The solution was then back loaded into a syringe stuffed with 225 mg ofcotton at the syringe tip and expelled to simulate common filteringmethods. The expelled solution (regardless of viscosity) was analyzedfor oxycodone content. The results for the prototypic formulation, thereference ER, ADF oxycodone formulation, and the reference ER, non-ADFoxycodone formulation are shown in Tables 5, 6, and 7.

TABLE 5 % Oxycodone extracted in 2 mL water Stirring time Sample Type oftablet 5 min 10 min 30 min Prototype Formulation Whole Tablet 6.3 8.212.7 4 Piece Cut 9.7 12.8 16.8 Reference ER, ADF Whole Tablet 4 4.8 7.9

TABLE 5 % Oxycodone extracted in 2 mL water Stirring time Sample Type oftablet 5 min 10 min 30 min 4 Piece Cut 5.7 7.2 10.6 Reference ER,Non-ADF Whole Tablet 4.6 6.8 11.8 4 Piece Cut 8 12.3 13.4

TABLE 6 % Oxycodone extracted in 5 mL water Stirring time Sample Type oftablet 5 min 10 min 30 min Prototype Formulation Whole Tablet 8.9 1432.7 4 Piece Cut 14.8 18.1 39.3 Reference ER, ADF Whole Tablet 5 6.913.5 4 Piece Cut 7.9 13.3 23.8 Reference ER, Non-ADF Whole Tablet 6.410.4 18.4 4 Piece Cut 12.7 17.8 33.2

TABLE 7 % Oxycodone extracted in 10 mL water Stirring time Sample Typeof tablet 5 min 10 min 30 min Prototype Formulation Whole Tablet 9.314.7 32 4 Piece Cut 14.9 21.2 43.3 Reference ER, ADF Whole Tablet 5.57.9 16.5 4 Piece Cut 8.3 10.6 28.1 Reference ER, Non-ADF Whole Tablet7.2 10.8 21.2 4 Piece Cut 12.8 21.9 36.7

Example 7: Preparation of Prototype #3

A third prototype of the disclosed formulation was prepared. A mixturecomprising high molecular weight hydroxypropyl cellulose (15-25% w/w),hydroxypropylmethyl cellulose (5-15% w/w), oxycodone hydrochloride(10-80 mg), and Mg stearate (0.1-0.4% w/w) was roller compacted to theappropriate ribbon thickness. The ribbons were milled to the appropriateparticle size, which were then dry blended with carbomer (1-4% w/w),polyethylene oxide (20-50% w/w), citric acid (5-15% w/w), and sorbitol(1-10% w/w). The blend was lubricated with Mg stearate (total of 1% w/win overall formulation), and the lubricated blend was compacted intotablets (250 mg) using an automated press. The tablets were humidifiedin a pan coater with clean steam for 2 hours at 30-50° C. and between65% to 99% relative humidity, dried at 20-60° C. for 2 hours, coated,and cured in a pan coater at 80° C. for 3 hours.

Example 8: Force Profile of Prototypic #3

The breaking point of the tablets prepared in Example 7 was determinedusing a Texture Analyzer model TA.XT. Plus (Texture Technologies Corp.).Force was applied diametrically to each tablet and the compressiondistance was recorded. As shown in FIG. 3, each tablet exhibited aspecific breaking point, which was generally less than about 300 N.

Example 9: Oxymorphone Formulation

A prototype of the disclosed formulation was prepared using oxymorphoneHCl as the active pharmaceutical ingredient and tested for abusedeterrence. A mixture comprising high molecular weight hydroxypropylcellulose (15-25% w/w), hydroxypropylmethyl cellulose (5-15% w/w) andoxymorphone hydrochloride (5-40 mg), and Mg stearate (0.1-0.4% w/w) wasroller compacted to the appropriate ribbon thickness. The ribbons weremilled to the appropriate particle size, which were then dry blendedwith carbomer (1-4% w/w), polyethylene oxide (20-50% w/w), citric acid(5-15% w/w), and sorbitol (1-10% w/w). The blend was lubricated with Mgstearate (total of 1% w/w in overall formulation), and the lubricatedblend was compacted into tablets using an automated press. The tabletswere humidified in a pan coater with clean steam for 2 hours at 30-50°C. and between 65% to 99% relative humidity, dried at 20-60° C. for 2hours, coated, and cured at 80° C. for 3 hours.

What is claimed is:
 1. An abuse deterrent solid dosage form comprisingat least one active pharmaceutical ingredient (API) having a potentialfor abuse or a pharmaceutically acceptable salt thereof, at least onehydrophilic plastomer having a molecular weight from 20,000 daltons to2,000,000 daltons, a carbomer, and a deliquescent plasticizer comprisingan organic acid and a sugar alcohol, wherein the solid dosage form ishumidified and is heated to a temperature from about 60° C. to about 90°C. for about one to three hours, and wherein the solid dosage formprovides extended release of the at least one API.
 2. The abusedeterrent solid dosage form of claim 1, wherein the at least onehydrophilic plastomer is a combination of hydroxypropyl cellulose,hydroxypropylmethyl cellulose, and polyethylene oxide.
 3. The abusedeterrent solid dosage form of claim 1, wherein the at least onehydrophilic plastomer is present in an amount from 30% to about 80% byweight of the solid dosage form.
 4. The abuse deterrent solid dosageform of claim 1, wherein the carbomer is present in an amount from about0.5% to about 10% by weight of the solid dosage form.
 5. The abusedeterrent solid dosage form of claim 1, wherein the organic acid iscitric acid, glutaric acid, malic acid, tartaric acid, or combinationthereof; and the sugar alcohol is sorbitol, xylitol, maltitol, orcombination thereof.
 6. The abuse deterrent solid dosage form of claim1, wherein the deliquescent plasticizer is present in an amount fromabout 10% to about 30% by weight of the solid dosage form.
 7. The abusedeterrent solid dosage form of claim 1, wherein the at least one API isan opioid or a combination of an opioid and a non-opioid analgesic. 8.The abuse deterrent solid dosage form of claim 7, wherein the opioid isoxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, ormorphine.
 9. The abuse deterrent solid dosage form of claim 1, whereinthe solid dosage form is humidified in a relative humidity of about 65%to about 85% at about 25° C.
 10. The abuse deterrent solid dosage formof claim 1, which further comprises at least one lubricant.
 11. Theabuse deterrent solid dosage form of claim 1, which further comprises afilm coating.
 12. The abuse deterrent solid dosage form of claim 1,which has an in vitro release of no more than about 80% of the APIwithin about 6 hours.
 13. The abuse deterrent solid dosage form of claim1, which deters abuse by breaking into a plurality of particles havingan average diameter of greater than about 250 microns when crushed,ground, or pulverized.
 14. The abuse deterrent solid dosage form ofclaim 1, which deters abuse by forming a viscous mixture or gel whencontacted with from about 1 mL to about 10 mL of an aqueous solvent. 15.The abuse deterrent solid dosage form of claim 1, wherein the at leastone API is oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine,or morphine; the at least one hydrophilic plastomer is a combination ofhydroxypropyl cellulose, hydroxypropylmethyl cellulose, and polyethyleneoxide; and the deliquescent plasticizer comprises citric acid andsorbitol.
 16. The abuse deterrent solid dosage form of claim 15, whereinthe least one hydrophilic plastomer is present in an amount from 30% toabout 80% by weight of the solid dosage form; the carbomer is present inan amount from about 0.5% to about 10% by weight of the solid dosageform; and the deliquescent plasticizer is present in an amount fromabout 10% to about 30% by weight of the solid dosage form.